In recent years a number of studies have suggested that the retention of numerous compounds is responsible for enhancing uremic conditions, not just the low molecular weight nitrogenous toxin. According to the European Uremic Toxin (EUTox) workgroup, these compounds, with a relatively diverse nature in terms of molecular weight and properties, are divided into two major groups: protein-bound solutes and middle molecules.
The molecular weight of middle molecules range from 500 to 60000 Da and consist mainly of low molecular weight proteins and peptides (LMWPs). Toxins covered in this class are β2-microglobulin (β2M), complement proteins (C3a and Factor D), leptins and pro-inflammatory cytokines. The effect of these toxins can complicate the patient's condition with end stage renal disease. For example, high plasma levels of β2M (50 fold or more than normal level) have been related to the formation of severely destructive and potentially fatal amyloid deposits, characteristic of dialysis-related-amyloidosis. Similarly, parathyroid hormone (PTH) accumulation in dialysis patients has been related to carpal tunnel syndrome, high blood pressure and secondary hyperparathyroidism.
The effectiveness of the current membrane-based dialysis process is very low in removing β2M (11.8 KDa) from the blood stream as it requires an increase in pore size of the membrane. The increase in pore size also results in an increase in undesirable loss of useful proteins such as albumin in addition to possible retake of harmful endotoxins from dialysate. For this reason, methods based on hydrophobicity and immunospecificity have been developed, but each of these methods has its own shortcomings. The method based on hydrophobic interaction is not specific. The size of the adsorbent has to be adjusted to prevent removal of albumin or similar proteins. A careful design of the adsorbent bed is required to prevent clogging because of granulocyte and platelet adhesion or damage to the blood cells, due to high shear forces if an adsorbent with very small pores (for high surface area and size exclusion) is used. Methods based on immunospecific antibodies also suffer from similar problems. Furthermore, there are high costs involved in the development and purification of the antibodies. In addition, methods based on absorbent beds or affinity columns may result in small particulate material contamination of the blood stream, which may lead to thrombi and pulmonary emboli formation. Both approaches lack the ability to meet the high throughput requirements associated with hemodialysis.
Thus, current options are deficient such that a better toxin (such as β2M) removal system for hemodialysis applications is desirable. In one study, a 5% improvement in mortality was achieved with only a 10% increase in β2-microglobulin removal. These studies point towards an even greater reduction in mortality with further reduction in β2-microglobulin.